2-halo-4-(aminoacetamido)-benzyl alcohols

ABSTRACT

4-(Amino-(polycarbon-lower-alkyl)-amino)-2-halobenzyl alcohols and lower-alkyl ethers thereof have schistosomacidal activity. The benzyl alcohols are prepared: by reduction of the corresponding benzaldehydes or lower-alkyl benzoates; by microbiological oxidation of the corresponding 4-substitutedamino-2-halotoluenes; or, for the compounds where polycarbonlower-alkyl is ethylene, by reducing the corresponding loweralkyl 4-(aminoacetylamino)-2-halobenzoates or by reducing the corresponding 4-(aminoacetylamino)-2-halobenzyl alcohols. The ethers are prepared by heating the benzyl alcohols with a loweralkanol in the presence of an acid.

StEltES Patent [191 Archer et all;

" Dec.'17,.'1974 22 Filed:

21 1 Appl, No.: 368,183

[ 2-HALO-4-( AMINOACETAMI I)O)-BENZYL 4 ALCOHOLS [75] Inventors: SydneyArcher, Bethlehem; David Rosi, East Greenbush, both of NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

June 8, 1973 [52] U.S. Cl... 260/562 N, 260/2472 A, 260/268 R,260/293.77, 260/326.3, 260/239 B, 424/244, 424/248, 424/250, 424/268,424/274 [5 ll Int. Cl. C07c 103/38 [58] Field of Search 260/562, 239',247.2, 268, 260/293.77, 326.3

[5 6] References Cited UNITED STATES PATENTS 3,520,930 7/1970 Clark etal. 260/562 Primary ExaminerHarry I. Moatz Attorney, Agent, orFirm-Elmer J. Lawson; Robert K; Bair ABSTRACT4-[Amino-(polycarbon-lower-alkyl)-amino1-2- halobenzyl alcohols andlower-alkyl ethers thereof have schistosomacidal activity. The benzylalcohols are prepared: by reduction of the corresponding benz aldehydesor lower-alkyl benzoates; by microbio logical oxidation of thecorresponding 4-substituted amino-2-halotoluenes; or, for the compoundswhere polycarbon-lower-alkyl is ethylene, by reducing the correspondinglower-alkyl 4-(aminoacetylamino)-2- halobenzoates or by reducing' thecorresponding 4- (aminoacetylamino)-2-halobenzyl alcohols. The ethersare prepared by heating the benzyl alcohols with a l'ower-alkanol invthe presence of an acid.

4 Claims, N0 Drawings .(polycarbon-lower-alkyl )-amino]-2-ha'lobenzyl vZ-HALOJHAMINOACETAMIDO)-BENZYL" I ALCOHOLS I COMPOSITIONS AND THEIRPREPARATION This application is a division of our copending applicationSer. No. 221,047, filed Jan. 26, 1972 and now U.S. Patent 3,819,707issued June 25, 1974, which in turn is a continuation-in-part of itscopending Ser. No. 42,876, filed June 2, 1970 and now U.S; Pat. No.3,714,167, issued Jan. 30, 1973, which in turn is a continuation-in-partof its copending application Ser. No. 664,628, filed Aug. 31, 1967 andnow US. Pat; No. 3,558,629, issued Jan. 26, 1971, which in turn is acontinuation-in-part of its copending'application Ser. No. 444,848,filed Apr. 3,379,620, issued Apr. 23, 1968.

This invention-relates to 4-aminobenzyl alcohol derivatives and toprocesses for their preparation.

The invention sought to bepatented in application Ser. No.-221,047, inits composition aspect, resides in the class of compounds which wedesignate 4-[amino- (polycarbon-lower-alkyl)-amino]-2-halobenzylalcohols and lower-alkyl ethers thereof. The tangible eml, 1965, now US.Pat. No.

lies widely; for example, in some. compounds the two amino groups areconnected by alkylene having a chain of two to six carbonatomsinclusive, optionally substituted by lower-alkyl, and having itsconnecting linkages on differentcarbon atoms, with the terminal aminobeing'primary, secondary or tertiary, and the other amino (directlyconnected to the benzene ring) bearing hydrogen or'lower-alkyl; in othercompounds the two amino groups are part of a piperazino ring, with theterminal amino (i.e., the 4-ring nitrogen of piperazino) beingunsubstituted or bearing various substituents, e.g., lower-alkyl,lower-alkenyl, lower-hydroxyalkyl, phenyl-(lower-alkyl), carbamyl,thiocarbamyl, lowercarbalkoxy, carboxy-(lower-alkanoyl), carboxy-(lower-alkenoyl),.etc. Also, these compounds canbear other low-molecularsubstituents, e.g., lower-alkyl, at one or more of the "remaining threeavailable ring positions, i.e., 3, 5 and/or 6. One of the best known andmost active of these 4-(aminoalk'ylamino)-2- halotoluenes is2-chloro-4-(2-diethylaminoe- .thylamino)toluene, preferably named as3-chloro-N-.

halobenzyl alcohol which comprises subjecting a 4- I [amino-(polycarbon-lower-alkyl )-amino]-2- halotoluene to the fermentativeenzymatic action of an organism capable of effecting oxidation of thel-methyl group to l-hydroxymethyl, said organism classified in theorders Moniliales, Mucorales, Sphaeriaeles, Sphaeropsidales,Melanconiales and Actinomycetales. We

alkyl)-amino]-2-halobenzaldehyde or lower-alkyl 4-[amino-(polycarbon-lower-alkyl)-amino]-2- halobenzoate with a reducingagent effective to reduce, respectively, benzaldehydes or lower-alkylbenzoates to benzyl alcohols. Said application Ser. No. 664,628, now US.Pat. No. 3,558,629, discloses and claims the intermediate 4-(1-piperazinyl)-2-halobenzaldehydes which are prepared by reacting a 3-(l-piperazinyl)-halobenzene with an Y(polycarbon-lower-alkyl)-amino]-2-halobenzyl N--R'NR"-formamide, where Ris lower-alkyl phosphorus oxyhalide.

Well known as schistosomacidal agents are a wide variety of4-[amino-(polycarbon-lower-alkyl)-amino]-2- halotoluenes which differfrom our 4-[aminoalcohols ,or ethers in having methyl instead ofhydroxymethyl or alkoxymethyl as'a substituent on the benzene ring orthoto halo and para to the aminoalkylamino substituent. The aminosubstituent amino-(polycarbon-lower-alkyl)- of these known 4-[ami'no-(Z-diethylaminoethyl)-4-methylaniline and perhaps better known asMirasan; other highly active and preferred members of this known classof compounds are l-(3-chloro-4-methylphenyl)piperazine [same as2-chloro-4 l-piperazinyljtoluene], l-( 3-chloro-4-methylphenyl)-4-methylpiperazine, maleic acid mono- 4-(3-chloro-4-methyl)piperazide and 2-chloro-4-{4- [6-(4tertiary-amylphenoxy)hexyll-1 -piperazinyl}- toluene. All of theseand'other heretofore known compounds having high sc'histosomacidalactivity required the presence of the methyl substituent on the benzenering, as well as the halo and amino-(polycarbon-lowe ralkyl)-aminosubstituents at ortho and para positions, respectively. Workers in thefield have reported that the methyl group cannot be replaced by anotherradical without losing the schistosomacidal activity.

We-have now found that compounds of this type where the ring methylsubstituent is replaced byhydroxymethyl, i.e.,4-[amino-(polycarbon-lower-alkyl)- arnino]-2-halobenzyl alcohols, or byloweralkoxymethyl not only have high schistosomacidal activity but alsoare more active as schistosomacidal agents in hamsters and less toxicthan the correspond-. ing methyl compounds.

Without limiting the generality of the foregoing, illustrative andpreferred embodiments of our 4-[aminoalcohols and lower-alkyl ethers arethose of formula I CH OR R-is hydrogen or lower-alkyl; Y is polycarbonloweralkylene; R, and R; are each hydrogen'or lower-alkyl,

lower-alkenyl or lower-hydroxyalkyl and can be the same or different; Rand R taken with N also compre hend saturated N-heteromonocyclicradicals having from five to six ring atoms, illustrated by piperidino,pyrrolidino, morpholino, piperazino, hexamethyleneimino andlower-alkylated derivatives thereof;- and, R is hydrogen, lower-alkyl,lower-alkenyl, lowerhydroxyalkyl, carbamyl, thiocarbamyl,lower-alkanoyl, lower-carbalkoxy, carboxy-(lower-alkanoyl), carboxy-(lower-alkenoyl) or phenyl-X-(lower-alkyl), where X is oxygen or adirect linkage. Here and elsewhere throughout this specification, itwill be understood the benzene ring of phenyl can bear any number andkind of substituents such as would occur to the man skilled in organicchemistry, e.g., such substituents, solely for illustration and withoutlimitation, including loweralkyl, lower-alkoxy, halo (chloro, bromo,iodo of fluoro), nitro, lower-alkylmercapto, loweralkanoylamino,lower-alkanoyloxy, lower-alkylamino, lower-alkenyl, and the like.

The compounds of formula I where NB is are disclosed and claimed in saidcopending application Ser. No. 42,876.

The above terms, as used throughout this specification, have thefollowing meanings, each of which are illustrated but without limitingtheir generality: loweralkyl means alkyl radicals having from one to sixcarbon atoms which can be arranged as straight or branched chains, e.g.,methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl andn-hexyl; polycarbon-lower-alkylenc means alkylene radicals having fromtwo to six carbon atoms inclusive and having its connecting linkages ondifferent carbon atoms, e.g., CH2CH2,

l --CH CHCH -CH CH CHCH v I CH2CH2CH2CH2, and lower-alkenyl" meansalkenyl radicals having from three to six carbon atoms, e.g., 2-propenyl(allyl), 2-methyl-2-propenyl, 2-butenyl, 3-butenyl and 2- hexenyl;lower-hydroxyalkyl" means hydroxyalkyl radicals having from two to sixcarbon atoms and having its connecting linkage and the hydroxyl group ondifferent carbon atoms, e.g., 2-hydroxyethyl, 2- hydroxypropyl,3-hydroxypropyl, 2-hydroxy-2- methylpropyl, 4-hydroxybutyl,2-hydroxy-2,2-

dimethylpropyl and G-hydroxyhexyl; "lowercarbalkoxy means carbalkoxyradicals where the alkoxy portion can be straightor branch-chained andhas from one to six carbon atoms. e.g., carbomethoxy, carbethoxy,carbo-n-propoxy, carbisopropoxy, carbo-nbutoxy and carbo-n-hexoxy;lower-alkanoyl" means alkanoyl radicals having from one to six carbonatoms which can be arranged as straight or branched chains, e.g.,formyl, acetyl, propionyl (n-propanoyl), isobutyryl(2-methoxy-n-propanoyl) and caproyl (nhexanoyl);' lower-alkenoyl meansalkenoyl radicals having from three to six carbon atoms, e.g., 2-propenoyl, 2methyl-2-propenoyl, Z-butenoyl, 3-

butenoyl and 2-hexenoyl. When NR,R of formula I or ll (below)comprehends saturated (lower-alkylated)- N-heteromonocyclic radicals,lower-alkyl radicals can be attached to any available ring-atom and canvary preferably from one to three in number, e.g., 2-

methylpiperidino, 3-ethylpiperidino, 4-methylpiperidino,2,6-dimethylpiperidino, 2,4- dimethylpiperidino,2,4,6-trimethylpiperidino, 3-npropylpiperidino, 2,2-dimethylpiperidino,2- methylpyrrolidino, 2,5-dimethylpyrrolidino, 2,3- dimethylmorpholino,2-ethylmorpholino, 2-

methylhexamethyleneimino, 2,7-dimethylhexamethyleneimino,4-methylpiperazino, 3-ethylpiperazino, 2,4,6-trimethylpiperazino, andthe like. I

The 4-[amino-(polycarbon-lower-alkyl)-amino]-2- halobenzyl alcohols andethers of our invention are useful in the free base form or in the formof their acidaddition salts, and both forms are within the purview ofthe invention, and are considered to be one and the same invention. Theacid-addition salts are simply a more convenient form for use; and, inpractice, use of the salt form inherently amounts to use of the baseform. The acids which can be used to prepare the acidaddition salts arepreferably those which produce, when combined with the free base,chemotherapeutically acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in chemotherapeutic doses ofthe salts, so that thebeneficial properties inherent in the free baseare not vitiated by side effects ascribable to the anions; in otherwords, the latter do not substantially affect the chemotherapeuticproperties inherent in the cations. ln practicing our invention, wefound it convenient to employ the hydrochloride or p-toluenesulfonatesalt. However, other appropriate chemotherapeutically acceptable saltswithin the scope of the invention are those derived from mineral acidssuch as hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid,sulfamic acid, and sulfuric acid; and organic acids such as acetic acid,citric acid, tartaric acid, lactic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, quinic acid, 3-hydroxy-2-naphthoic acid, pamoic acid (2,2- dihydroxy-l ,l-dinaphthylmethane-3,3 -dicarboxylic acid), naponic acid(l,S-naphthalenedisulfonic acid), and the like, giving the hydrobromide,hydriodide, nitrate, phosphate, sulfamate, sulfate, acetate, citrate,tartrate, lactate, methanesulfonate, ethanesulfonate,

'benzenesulfonate, quinate, 3-hydroxy-2-naphthoate,

pamoate and naponate, respectively.

The acid-addition salts are preparedpreferably by reacting the free baseand acid in an organic solvent, e.g., ethanol, acetone, etc., in whichcase the salt separates directly or can be obtained by concentration ofthe solution.

Although chemotherapeutically acceptable salts are preferred, allacid-addition salts are within the scope of our invention. Allacid-addition salts are useful as sources of the free base form even ifthe particular salt per se is not desired as the final product, as forexample when the salt is formed for purposes of purification oridentification, or when it is used as an intermediate in preparing achemotherapeutically acceptable salt by ion exchange procedures.

- ties, and by the correspondence of calculated and found values for theelementary analyses for representative examples.

The manner of making and using our invention will 7 now be generallydescribed so as to enable the'person skilled in the art of organicchemistry to make and use the same. l

FINAL PRODUCTS FROM CORRESPONDING. BENZALDEHYDES OR LOWER-ALKYLBENZOATES This process utilizes as intermediates 4-[amino-'(polycarbon-lower-alkyl)-amino]-2- halobenzaldehydes orlower-alkyl-4-[amino- (polycarbon-lower-alk-yl-)-aminol-2-halobenzoates,which areprepared'by generally known procedures illustrated in thespecific exemplary disclosure below or, in the case of the4-aminoalkylamino-2- halobenzaldehydes, by another process hereinbelow'described. The process comprises reacting the 4-aminoalkylamino-2-halobenzaldehyde or lower-alkyl4-aminoalkylamino-Z-halobenzoate with a reducing (lower-alkyl).

.aminoacetylamino-2-halobenzyl alcohols, which also where hal, R, R R RM115 have the meanings given above for formula I, with a reducing agenteffective to reduce lower-alkyl benzoates' to benzyl alcohols andaminoacetamides to aminoethylamines. Suitable reducing agents are thosegiven above for the reduction of lower-alkyl benzoates to benzylalcohols. We preferably used an alkali aluminum hydride, e.g., lithiumaluminum hydride in an inert solvent, e.g., tetrahydrofuran, in thepresence of a suitable catalyst, e.g., aluminum trichlorideibestresultswere obtained using lithium aluminum hydride, tetrahydrofuran andaluminum chloride, and keeping the reaction temperature below 0C.,preferably between l5C. and -5C. Alternatively, the same reduction canbe carried out but using instead of the benzoates of formula II thecorresponding benzyl alcohols, i.e., CH Ol-l in place of CO0- Theseintermediate 4- are useful as local anesthetic agents, as determined bystandard pharmacological evaluation procedures, can be prepared from thecorresponding 4-aminoacetylamino-2-halotoluenes by using our.microbiological oxidative procedure described hereinabove.

-The intermediate4-aminoacetylamino-2-halotoluenes are convenientlyprepared in two generally known steps from the corresponding known4-amino-2- halotoluenes, that is, by first reacting a 4-amino-2- agenteffective to reduce benzaldehydes or lower-alkyl benzoates,respectively, to benzyl alcohols. The reduction can be carried out bothby catalytic hydrogenation and by chemical methods. Catalysts suitablewhen catalytic hydrogenation is used include Raney nickel, platinum, orpalladium. Suitable chemical reducing agents includealkali aluminumhydrides, e.g., lithium aluminum hydride; alkali borohydrides, e.g.,sodium borohydride; an alkali metal and a lower alkanol, e.g., sodiumand ethanol. Also, the benzaldehydes can be reduced to the benzylalcohols using iron and acetic acid or isopropylalcohol and aluminumisopropoxide. In practic ing our invention, we preferably used lithiumaluminum hydride in ether or tetrahydrofuran in reducing thebenzaldehydes and sodium borohydride in a lower alkanol, e.g., ethanolor methanol, with or without water, in reducing thelower-alkyl'benzoates.

A modification of this process comprises reacting a lower-alkyl4-aminoacetylamino-2-halobenzoate, e.g.,

without limiting the generality of the foregoing, a low- 000-(lower-alkyl) I 2- 2 1 2 I 0 II halotoluene with chloroacetyl chlorideto form a 4'- (chloroacetylamino)-2-halotoluene which is then reactedwith ammonia or appropriate amine of the formula HNR R (R and R definedabove) to yield the 4-(R R N-acetylamino)-2-halotoluene.

' acid. This reaction is conveniently carried out by heater-alkyl4-aminoacetylamino-2-halobenzoate of the formula ll ing the basic benzylalcohol as its acid-addition salt,

e.g., di(p-,toluenesulfonate), in the lower-alkanol at its boiling pointto dissolve the benzyl alcohol salt and allowing the resulting solutionto cool whereupon the basic lower-alkyl ether separates as itsacid-addition salt.

EXAMPLE 1 Fermentative enzymatic oxidation of 2-chloro- 4-( lpiperazinyl)toluene to 2-chloro-4-(l-piperazinyl)- benzyl alcohol wasaccomplished as follows: Four 10 liter fermentations employingAspergillus sclerotiorum (S WRI A available at Sterling-WinthropResearch Institute, Rensselaer, NY.) in sterile soy-dextrose me dium ofthe following composition were'carried out.

Dextrose 1000 g. Soybean meal g. Yeast 50 g. NaCl 50 'g.

-Continued v MgSO,.nH O 2.5 g. Na1-1 PO J-l O 13.8 g. Na HPO,.121-1 O301 Ta water 9.5 iters p adjusted to 7.3 with lON l-lCl; autoclave at120c. and 15 psi for 15 minutes.

The stock culture was initially grown at 26C. on slants in a nutrientmedium (e.g., maltose, 40 g./liter, and

Proteose Peptone No. 3, 1 g./liter) in 22 X 175 mm.

tubes for 10 to 14 days. These slants were used to prepare seed for the10liter fermenters as follows: Sterile distilled water (10 ml.) wasadded to a slant and the spores and some vegetation growth were scrappedwith a sterile hooked needle. The resulting suspension was added to a2-liter flask containing 700 ml. of sterile soydextrose medium of thefollowing composition:

Soybean meal Dextrose Yeast NaCl K HPO Ta water adjusted to 6.4 with lONl lCl rior to autoclaving at 121C. and psi for 15 minutes These cottonplugged flasks were incubated at 26C.

I for approximately 70 hours on a rotary shaker with a made basic with0.2 ml. of N sodium hydroxide solution and extracted with methylenedichloride. The extracts were evaporated to dryness and the residuesdissolved in 3 ml. of methylene dichloride. Aliquots (20 ,ul) weretransferred to thin-layer silica gel plates impregnated with 1 percentof a phosphor (e.g., Radelin I GS-l The plates were developed in asolvent containing 8: 1:1 parts by volume of CH CH :CH OH:N(C H Thecomponents were viewed as bluespots on a yellow fluorescent background.Under these conditions, the Rf value of the intermediate toluenederivative was 0.46 and that of the corresponding benzyl alcohol was0.36.

' Isolation The fermentations were terminated by the addition of 130 ml.of ION NaOH and each tank was extracted with methylene dichloride (2 Xliters). The extracts were reduced under vacuum and.

combined. Further reductin in volume resulted in a yellow cyrstallineprecipitate weighing 150 g. Thin layer chromatography of this materialshowed traces of 2- chloro-4-( l-piperazinyl)toluene with the majorcomponent chromatographically identical with a sample of 2- chloro-4-(l-piperazinyl)benzyl alcohol prepared by reduction of the corresponding2-chloro-4-(lpiperazinyl)benzaldehyde (Example 10D, U.S. Pat. No.3,379,620).

Purification The material was recrystallized from ethyl acetate about800 ml.). An insoluble fraction (4.5 g.) was filtered off; this materialwas probably a salt of the product since in the'above basic TLC systemit behaved like 2-chl0ro-4-( l-piperazinyl)benzyl alcohol. On coolingthe filtrate in an ice bath, g. of cream-colored cyrstalline2-chloro-4-( lpiperazinyl)benzyl alcohol, m.p. 120122C. (corr.), wasobtained. A second crop of 23.5 g. was obtained from the mother liquor.

C], 15.64. Cl, 15.44.

Infrared, ultraviolet and nuclear magnetic resonance spectral data ofthe above product show it to be identical with the product obtainedchemically by reduction of the corresponding 2-chloro-4-( 1-piperazinyl)benzaldehyde.

EXAMPLE 2 Fermentative enzymatic oxidation of 2-chloro- 4-(2-diethylaminoethylamino)toluene to 2-chloro-4-(2- diethylaminoethylamino)benzyl alcohol was carried out following the procedure described 'inExample 1, using one l0-liter fermenter, Aspergillus sclerotiorum (SWRIA a sterile soy-dextrose medium of the following compositions Dextrose800 g. Soybean meal g. Yeast 50 g. NaCl 50 g. MgSOJH O 2 g.NiiglIPO4-7Hz0 193 g. NaH PO .H O 40 g. Ta water 9.5 liters p of about 7prior to autoclaving at 120C. and 15 lbs. psi for 15 minutes,

161 g. of 2-ehloro-4-(Z-di'ethylaminoethylamino)toluene hydrochlorideadded in 3-15 g. portions over a period of 8 days, a conversiontemperature of 29-30C., an aeration rate of 5 liters/minute, anagitation rate of 450 rpm, 150 ml. of 10N sodium hydroxide solution toterminate the fermentation, and two 20-liter portions of methylenedichloride to extract the product. A TLC on the extract showed goodconversion to the corresponding benzyl alcohol, along with some of thecorresponding 2-chloro-4-( 2-diethylaminoethylamino)benzaldehyde, asshown by spraying the TLC plate with 2,4-dinitrophenylhydrazine. Themethylene dichloride extract was concentrated in vacuo to an oil residuewhich was taken up with 200 ml. of anhydrous methanol. To this solutionwas added sodium borohydride in 2 g. portions until a TLC showed no morealdehyde to be present (total of 6 g. of NaBl-l, added) and acorrespondidng increase in the. amount of the corresponding benzylalcohol. The methanol was removed in vacuo and the residue taken up in500 ml. of chloroform. This solution was washed several times withdistilled water and the chloroform removed in vacuo. The remainingcrystalline material was washed with n-hexane to yield 93 g. of thewhite crystalline product, 2-chloro-4-(2-diethylaminoethylamino)benzylalcohol, m.p. 66.067.4C. (corr.). A second crop weighing 13.5 g. wasobtained from the mother liquor.

Anal. Cal'cd. for C H clN O. N, 10.91.

Found: N, l 1.09.

Infrared spectral data of the above product show it to be identical withthe product obtained by chemical methods as described hereinbelow, e.g.,by reduction of ethyl 2-chloro-4-(Z-diethylaminoethylamino)- benzoate(Example 3A) and by reduction of ethyl 2-chloro-4-(diethylaminoacetamido )benzoate (Example 4A).

EXAMPLE 3 A. 2-Chloro-4-(Z-diethylaminoethylamino )-benzyl alcohol Asolution of 2.5 g. of ethyl 2-chloro-4-(2-diethylaminoethylamino)benzoate in 35 ml. anhydrous ether was added toaslurry of 350 mg. lithium aluminum hydride in 75 ml. ether at roomtemperature. The

reaction mixture was refluxed gently for 30 minutes, allowed to cool,and treated with an excess of 35 percent aqueous sodium hydroxidesolution. The layers were separated and the aqueous layer extracted withether. The ether extract was washed with water, dried over anhydrousMgSO and concentrated to an oil weighing about 3 g. Chromatographicpurification of' the oil on a silica gel column (50 g., 2.5 X 25 cm.)developed with ether containing 5 percent triethylamine yielded 1 gramof material melting at 626'5C. When recrystallized once from abenzene-n-hexane mixture,

there was obtained 0.9 g. 'of 2-chloro- 4-(2-diethylaminoethylamino)-benzyl alcohol, m.p.

65.867.0C. (corn).

. Anal. Calcd. for cmu clmo; N, 10.91; Cl, 13.81. Found: Cl, 13.36

Reaction of 2-chloro-4-(2-diethylaminoethylamino)- benzyl alcohol withacetic anhydride, propionic anhydride, benzoyl chloride,3,5-dinitrobenzoyl chloride, 4-ethoxybenzoyl chloride orunsubstituted-phenyl isocya'nate yields the following respective2-chloro-4-(2- diethylaminoethylamino)benzyl ethers: acetate,propionate, benzoate, 3,5-dinitrobenzoate, 4- ethoxybenzoate orcarbanilate'.

B. The above intermediate ethyl 2-chloro-4-(2-diethylaminoethylamino)benzoate was prepared as follows: Twenty-sixgrams of ethyl 4-amino-2- chlorobenzoate and 52 g. of freshly distilled2- over anhydrous MgSO, and concentrated to an oil weighing 8 grams. Theoil in anhydrous ether was passed through a silica gel column (100 g.,2.5 X 50 em.) using additional ether as the eluunt to yield 5 g. of oilwhich was dissolved in I00 ml. of boiling absolute .10 ethanol andtreated with cooling, the crystalline solid that separated wascollectedand recrystallized from absolute ethanol to yield' 7 g. of ethyl2-chloro-4-(2-diethylaminoethylamino) benzoate as its picrate, m.p.-149.5-l50.5C.

Anal. Calcd. for

is zi z r s a a r N. 13.27; Found:

6.72. N, 13.30; Cl, 6.98.

The picrate was. decomposed with aqueous ssodium and the residuedistilled to yield 2.5 g. of ethyl 2-chloro-4-(Z-diethylaminoethylamino)benzoate, ;a light colored oilboiling at l90- l94C. at 0.5 mm.

EXAMPLE 4 A. 2-Chloro-4-(2-diethylarninoethylamino)benzyl alcohol fromethyl 2-chloro-4-(diethylamino'acetamido)-benzoate A solution of 23.4 g.of aluminum chloride in 300 ml. of tetrahydrofuran was added all atonce, but cautiously, to a mixture of 52 g. of lithium aluminum hydridein 2,000 ml. of tetrahydrofuran and the mixture was cooled to l2C. Thefree base from 117 g. of ethyl2-chloro-4-(diethylaminoacetamido)benzoate hydrochloride was dissolvedin 200 ml. of tetrahydrofuran and the solution was added with efficientstirring over a period of minutes to the solution oflithium aluminumhydrideand aluminum chloride/The temperature during the addition wasmaintained at -l2C. to 8C. using a mixture of solid carbon dioxide andacetone. The reaction was stirred for 6 hours at 12C. to 6C. and thencarefully hydrolyzed with 165 ml. of 35 percent sodium hydroxidesolution. In order to break the emulsion, 20

' g. of finely ground potassium hydroxide was added.

The mixture was filtered and the filter cake was washed twice withtetrahydrofuran. The filtrate was concentrated in vacuum. The residue,84 g., was dissolved in ml. benzene and then ml. n-pentane was added.The resulting slightly yellow crystalline product was collected andfound to weigh 44.5 g. (46 percent), m.p. 6467" C. Recrystallizationfrom benzene-n-pentane, using decolorizing charcoal,.afforded 44 g. of2-chlor-i- 4-(2-diethylaminoethylamino)benzyl alcohol, m.p. 6668C.

Following the procedure of Example 4A using a molar equivalent quantityof the corresponding loweralkyl, e.g., ethyl, 2-halo-4-[di-(lower-alkyl-)aminoacetylamino]benzoate, the following 2-halo-4-[2-di-(lower-alkyl)aminoethylamino]benzyl alcohols are obtained: halo isBr and lower-alkyl is ethyl; halo is Cl and lower-alkyl is n-butyl; halois Cl and lower-alkyl is methyl; and, halo is Cl and lower-alkyl isn-hexyl.

B. The intermediate ethyl 2-chloro-4-(diethylaminoacetamido)benzoateused in Example 4A was prepared as follows: A mixture of 133 g. of ethyl2-chloro-4-(chloroacetamido)benzoate and 106 g. of diethylamine in 1liter of dry benzene was refluxed for 4 hours. The reaction mixture wasconcentrated to about half of its volume and washed with water. Theorganic layer was extracted with-dilute hydrochloric acid. After washingthe acidic extracts with ether, the soluextracts were dried overanhydrous calcium sulfate and then concentrated. The residue wasdissolved in isopro- 4.5 g. of picric acid After pyl alcohol and thehydrochloride was prepared by adding one equivalent of concentratedhydrochloric acid, followed by ether until the solution was almostcloudy. After cooling, the crystalline product was collected to yield144 g. (86 percent) of ethyl 2-chloro-4- (diethylaminoacetamido)benzoatehydrochloride, m.p. l50l5 1C.

C. The intermediate ethyl 2-chloro-4- (chloroacetamido)benzoate used inExample 413 was prepared as follows: To a refluxing solution of 115 g.of ethyl 4-amino-2-chlorobenzoate in 350 ml. ethylene dichloride wasadded slowly a solution of 68 g. of chloroacetyl chloride dissolved in210 ml. ethylene dichloride. The mixture was refluxed for 90 minutes andthen diluted with 1 liter of n-pentane. After cooling in therefrigerator overnight, the precipitate was collected and washed wellwith n-pentane to yield 133 g. (83 percent) of ethyl2-chloro-4-(chloroacetamido)-benzoate,

m.p. ll9-l22C.

EXAMPLE A. 2-Chloro-4-(4-ethyl-l-piperazinyl)benzyl alcohol from2-chloro-4-(4-ethyl-l-piperazinyl)benzaldehyde .To a solution containing4.0 g. of 2-chloro-4-(4- ethyl-l-piperazinyl)benzaldehyde (see Example5B) in 45 ml. of absolute ethanol was added 10 ml. of a 50 percentsolution of sodium borohydride in ethanol. The resulting mixture wasstirred at room temperature for 1 hour and then allowed to stand overthe weekend. After removal of the alcohol by distillation in vacuo, 2Omlfof percent aqueous sodium hydroxide solution was added and theresulting mixture was extracted three times with ether. The etherextract was dried over anhydrous magnesium sulfate and the ether removedto yield an oil which solidified on cooling. The solid wasrecrystallized twice from benzene-n-hexane,'using decolorizing charcoalthe second time, and dried at 75C. for 3 hours at 20 mm. to yiled 1.8 g.of 2-chl0ro-4-(4- ethyl-l-piperazinyl)benzyl alcohol, m.p. 96.899.0 C.(corr.). I I

Anal. Calcd. for C H CIN O: Found:

Cl, 13.91: Cl, 13.78;v

' water was added 8 g. of zinc dust (90 percent) in two portions, whilecooling the reaction mixture to keep the temperature below 70C. Theexcess zinc dust was filtered off and washed with ml. of water; 2.4 ml.of concentrated hydrochloric acid was added to the filtrate. Theresulting solution was added to a solution obtained by dissolving 6.0 g.of' l-(3-chlorophenyl)-4- ethylpiperazine in a mixture of 4.0 ml. ofconcentrated hydrochloric acid and 0.5 ml. of water followed by additionof 2.3 ml. of 37 percent aqueous formaldehyde, the first solution beingadded to the second immediately after addition of the formaldehyde toform the second solution. The reaction mixture was then allowed to standat room temperature for 2 days, 50 ml. of saturated'solution of sodiumchloride in water was added, and the resulting mixture was neutralizedto a pH of 6.87.0 with ammonium hydroxide, whereupon a gummy yellowprecipitate separated. The residue was stirred in an ice bath for 30minutes and the resulting gummy precipitate was collected. To theprecipitate was added ml. of water and 25 ml. of ammonium hydroxide, themixture was heated below its boiling point for ten minutes, cooled andextracted four times with 100 ml. of ether. The ether extract was driedover anhydrous magnesium sulfate and the ether removed to yield, as aviscous yellow oil, 4.0 g. of 2-chloro-4-(4-ethyl-l-piperazinyl)benzaldehyde; Infrared spectral analysis of thiscompound showed it to have a carbonyl group. Also, it was converted intoits thiosemicarbazone, m.p. 223.0223.5C. (corr.) with decomposi- Anal.Calcd. for C H CIN S: 0.88, S, 9.84

Found: 1.18; S 9.46.

- 'C. The intermediate 1-(3-chlorophenyl)-4-ethylpiperazine used inExample 58 was prepared as follows: A mixture containing 15 g. of1-(3-chlorophenyl)piperazine, 6 ml. of ethyl bromide and 100 ml. ofbenzene was refluxed for three hours. The white solid[1-(3-chlorophenyl)piperazine hydrobromide] that separated was filteredoff, 15 ml. of ethyl bromide was added to the filtrate and refluxing wascontinued for another 4 hours. The mixture was stirred at roomtemperature overnight and another 3.5 g. of 1-(3-chlorophenyl)piperazinehydrobromide was filtered off. The filtrate was concentrated in vacuoand the remaining oil was dissolved in anhydrous ether and filteredthrough infusorial earth (Super-Cel). To the filtrate was added 7.9 ml.of 9.7N ethanolic'hydrogen chloride. The resulting white precipitate wascollected, air-dried and recyrstallized from about 400 ml. of acctone toyield 5.0 g. of l-(3-chlorophenyl)-4-ethylpiperazine hydrochloride, m.p.206208C., after drying at 70C. at 20 mm. for 1 hour. A second crop of1.5 g.,

mp. 208 209.C., was obtained by concentrating the filtrate to 100 ml.For analysis, a 0.5 g. sample of the first crop was placed in an oven atC. and 20 mm. overnight.

Anal. Calcd. for C H C'lN l-lCl: N, 10.72. Found: N, l0.78.

EXAMPLE 6 A. 2-Chloro-4-(2-diethylaminoethylamino)-3,5-

hol as its di-(p -toluenesulfonate), 154.0 154.6C.

(corr.) with decomposition.

Anal. Calcd. for C l-l ClN O2C H O S: C, 55.35;

H, 6.57; N, 4.45; S, 10.19. Found: C, 55.15; H, 6.56; N, 4.22; S. 10.09.

B The above intermediate prepared following the procedure described inExample 58 using 25.0 g. of sodium -nitro-o-tolucncsulfonate, 4.4 g. ofammonium chloride, 100 ml. of water, 20.0 g. of zinc dust (90 percent),62 ml. of wash water, 4.4 ml. of concentrated hydrochloric acid, 22.0 g.of 3-( Z-dietliylaminoethylamino )-2,4-dimethylchlorobenzene, a mixtureof 10 ml. of concentrated hydrochloric acid and 30 ml. of water, and 5.7ml. of 37 percent formaldehyde solution. There was thus obtained, as anoil, 7.5 g., of 2-chloro-4-(Z-diethylaminoethylzimino)-3,5-

dimethylbenzaldehyde.

, C. The intermediate 3-(2-diethylaminoethylamino)-2,4-dimethylchlorobenzne used in Example 68 was prepared as follows: Amixture containing 22 'g. of

' 3-chloro-2,6-dirnethylaniline, 15.5 g. offreshly distilled2-diethylaminoethyl chloride and 100 ml. of benzene was refluxed for 27hours. The reaction mixture was concentrated in vacuo and the viscousoily residue was heated at 100C. and 0.1 mm. To the residue was addedabout 400ml. of ether and the mixture was cooled in a bath of solidcarbon dioxide and acetone, whereupon the gummy product solidified. Thesolid was collected and recrystallized from isopropyl alcohol-ether toyeild 5.4 g. of 3-(2-diethylaminoethylamino)-2,4-dimethylrchlorobenzene, m.p. 104106C.

Anal. Calcd. for C H- ClN- N, 9.62. Found: N, 9.58.

D. 2-Chloro-4-(2-diethylam'inbethylamino)-benzyl alcohol (0.8 g., m.p.64.,065.5C.) was obtained from2-chloro-4-(Z-diethylaminoethylamino)benzaldehyde (3g) following theprocedure described above in Example 6A using ml. of methanol and l g.of sodium bore-hydride.

EXAMPLE 7 Fermentative enzymatic oxidation of 2-chloro-4-(2-diethylaminoethylaniino)-3,5-dimethyltoluene to 2-chloro-4-(2-diethylaminoethylamino)-3,5- dimethylbenzyl alcohol wascarried out following the procedure described in Example 2 using 6.5 g.of 2- chloro-4-'(Z-diethylaminoethylamino)- 3,5-

dimethyltoluene hydrochloride and a reaction period of 3"days, all otherreaction conditions being the same.

as in Example 2; The product was isolated as follows: The oily residueafter evaporation of the methylene dichloride was mixed with 30 g. ofsilica gel and placed on a 150 g. silica gel column (3.7 X 21 cm.) andthe column was developed using increasing amounts of ether in n-hexaneand finally with increasing amounts of methanol in ether, ,allsolvents-containing 0.5 per-- cent triethylamine. The fractionscollected with 99.5 percent ether and 0.5 percent triethylamine werecom- 2-chloro-4-(2- diethylaminoethylamino)-3,S-diethylbenzaldehyde wasbined and evaporated to yield, asan oil, 2-chloro-4-(2-diethylaminoethylamino)-3 ,S-dimethylbenzyl alcohol.

I EXAMPLE 8 3-Chloro-N-(2-diethylaminoethyl)-4-methoxymethyl-2,6-dimethylaniline When 2-chloro-4-(2-diethylaminoethylamino)-3,5-dimethylbenzyl 1 alcohol (152 g.)dissolved in ethanol (150 ml.) was mixed with p-toluenesulfonic acidmonohydrate (128 g.) in'ethanol (400 ml.), there separated a whitecrystalline precipitate of 2-chloro-4-( 2-diethylaminoethylamino)-3,5-dimethylbcnzyl alcoholdi-(p-tolucnesulfonatc). When the latter was dissolved in boilingabsolute methanol, the hot solution treated with decolorizing charocaland filtered, and the filtrate allowed to cool, there separated3-.chloro-N-(2- diethylaminoethyl)-4-methoxymethyl-2,6-

dimethylaniline di-(p-toluenesulfonate) (1l9g.), m.p.

153.0- 155.8C. (corr.) with decomposition.

Anal. Calcd.

v Found: S, 10.21; C], 5.61.

3-Chloro-N-(2 diethylaminoethyl)-4- methoxymethyl-2,6-dimethylaniline infree base form was obtained by dissolving its di-(p-toluenesulfonate) inwater,-making the aqueoussolution alkaline with aqueous sodium hydroxidesolution, extracting the free base form with methylene dichloride,removing the methylene dichloride, and drying in vacuo at 65C.

. Following the foregoing procedure using, in place of boiling methanol,boiling n-propanol, n-butanol or nhexanol to dissolve the 2-chloro-4-(2-diethylaminoethylamino)-3,5-dimethylbenzyl alcoholdi-(p-toluenesulfonate), there is obtained the following ethers first inthe form of their di-(p-toluenesulfonates) and then in their freebaseforms: 3-chloro-N-(2-diethylaminoethyl)-2,6-dimethyl-4-npropoxymethylaniline,4-n-butoxymethyl-3 chloro-N (2-diethylaminoethyl)-2,6-dimethylaniline or3-chloro- N-(2-diethylaminoethyl) 4-n-hexoxymethyl-2,6-

dimethylaniline, respectively. Similarly, following the above procedureusing, in place of 2-chlor0-4-(2-diethylaminoethylamino)-3,S-dimethylbenzyl alcohol,

dure described in Example 8-usin'g boiling ethanol insteadof boilingmethanol. Thus, from 1 g. of 2-chloro- 4-( 2-diethylaminoethylamino )-3,S-dimethylbenzyl al-' cohol and 1.2 g. p-toluenesulfonic acid monohydrate, there was obtained 1.5 g. of 3-chloro-4-ethoxymethyl- 15 N-(2-diethylaminoethyl)-2,6-dimethylaniline di-(p-toluenesulfonate), m.p.l40l42C.

Fermentative enzymatic oxidation of 2-chloro-4-(diethylaminoacetylamino)-3,5-dimethyltoluene (l4g.) to2-chloro-4-(diethylaminoacetylamino)-3,5- dimethylbenzyl alcohol wascarried out following the procedure described in Example 2 using areaction period of 2 weeks, a conversion temperature of 28-29C., anagitation rate of 400 rpm, an aeration rate of 4 liters per minute, and100 ml. of [N sodium hydroxide solution to terminate the fermentation.The residue after evaporation of the methylene dichloride was dissolvedin 150 ml. ofa mixture of nine parts (by volume) of methanol and onepart of water and the solution extracted with n-hexane. Themethanol-water phase was evaporated in vacuo and dried to a thick oilyresidue which was dissolved in ether. The ether solution was treatedwith decolorizing charcoal, filtered and the filtrate cooled. Thecrystalline precipitate that separated was collected and purified byrecrystallization from ethyl acetate-ether to yield 3.7 g. of 2-chloro-4-(diethylaminoacetylamino) 3,5- dimethylbenzyl alcohol, m.p.l39-l40C.

Anal. C alcd. for C ,,H -,ClN O Found:

Following the reductive procedure of Example 4A2-chloro-4-(diethylaminoacetylamino)-3,5- dimethylbenzyl alcohol isreduced to yield 2-chloro-4- (diethylaminoethylamino)-3,5-dimethylbenzyl alcohol.

When tested for local anesthetic activity by the standard intradermalinjection method in guinea pigs, 2-chloro-4-(diethylaminoacetylamino)-3,5- dimethylbenzyl alcohol was foundto produce average durations of anesthesia of ll and 14 minutes at doseconcentrations of 0.4 and 0.8 percent respectively.

2-bromo-4-( 2-diethylaminoethylamino)benzyl alcohol,

2-chloro-4-(2-ethylaminoethylamino)benzyl alcohol,

2-chloro-4 [2-( l-piperidinyl)ethylamino]benzyl alcohol or2-chloro-4-(2-dimethylaminoethylamino)benzyl alcohol.

The foregoing intermediate 4-(aminoaeetylamino)- 2-halotoluenes areprepared from the corresponding known 4-amino-2-halotolu'enes byreacting the latter with chloroacetyl chloride to form the corresponding4-(chloroacetylamino)-2-halotoluenes which are then reacted with theappropriate amine, e.g., diethylamine, to form the corresponding4-(aminoacetylamino) compounds, e.g., 4-(diethylaminoacetylamino)-2-halotoluenes using diethylamine. The preparation of these intermediatesis illustrated as follows for the preparation of2-chloro-N-(diethylaminoacetyl)-3,5- dimethyltoluene from3-chloro-3,4,,6'trimethylaniline: To a stirred refluxing solution of 8g. of 3-chloro-2,4,6- trimethylaniline in 25 ml. of ethylene dichloridewas added dropwise a solution of 5.46 g. of chloroacctyl chloride in 15ml. of ethylene dichloride. The resulting reaction mixture was refluxedwith stirring for three hours, cooled, diluted with 100 ml. ofn-pentane, and stirred cold for 30 minutes. The resulting precipitatewas collected, washed with n-pentane, recrystallized from absoluteethanol-n-pentane and dried in vacuo at C. 'to yield 7.8 g. of2-chloro-4- (chloroacetylamino )-3,5-dimethyltoluene, m.p.

l67l68C. A, mixture of said 4-(chloroacetylamino) compound with 6.94 g.of diethylamine and 75 ml. of benzene was refluxed for 4 hours,concentrated to about one-half the original volume, washed with water.

and extracted with dilute aqueous hydrochloric acid. The acidic .extractwas washed with ether, made basic with concentrated ammonium hydroxideand extracted with ether. The ether extract was dried over anhydroussodium sulfate, and heated in vacuo to remove the ether, thereby leaving8.7 g. of 2-chloro-4- (diethylaminoacetylamino)-3,5-dimethyltoluene. Asolution of this compound in isopropyl alcohol was treated with 2.59 ml.of concentrated hydrochloric acid in isopropyl alcohol, the reactionmixture warmed and then allowed to cool, whereupon the whitehydrochloride separated. The mixture was diluted with absolute ether andthe precipitate was collected, recrystallized from absoluteethanol-ether, dried in vacuo at 60C. to

yield 6.0 g. of 2-chloro-4-(diethylaminoacetylamino)- I3,5-dimethyltoluenc as its hydrochloride, -m.p. l50.0l54.0C. (corr.).[Anal calcd. for C H CIN OLHCIZ C1, 22.1:N, 8.77. Found: C1, 22.39; N,8.80]. The following intermediate 4- (aminoacetylamino)-2-halotoluenesare similarly prepared in two steps using the appropriate 4-amino-2-halotoluene, chloroacetyl chloride and tertiaryor secondary-amine:2-chloro-4- (diethylaminoacetylamino)toluene, 2-bromo-4-(diethylaminoacetylamino)toluene, 2-chloro-4-(ethylaminoacetylamino)toluene, 2-chloro-4-(lpiperidinylacetylamino)-toluene and 2-chloro-4-(dimethylaminoacetylamino )toluene.

EXAMPLE 1 l 2-Chloro-4- (Z-diethylaminoethylamino)-3,5-

dimethylbenzyl alcohol as its cyclohexanesulfamate was prepared byadding a solution of 4.45 g. of N-cyclohexylsulfamic acid in 45 ml. ofacetone to a solution of 7.1 g. of said benzyl alcohol in 50 ml. ofacetone whereupon the salt crystallized immediately, cooling the mixtureto 5C., collecting the precipitate, washing it with a little acetone andether, and drying it in vacuo at C. to yield 10.5 g. of saidcyclohexanesulfamate, m.p. C.

I diethylaminoethyl)methylaminoltoluene 3-Chloro-N-(2-diethylaminoethyl)-4- isopropoxymethylQ,-dimethylanilihedi-(p-toluenesulfonate) was prepared from the corresponding 4'-methoxymethyl compound (Example 8) as follows: A solution containing 10g. of 3-ehloro-N-(2- diethylaminoethyl)-4-methoxymethyl-2,6-

small amount of the corresponding 2-chloro-4-lt2- dimethylanilinedi-(p-toluenesulfonate) in 100 ml. of

hot isopropyl alcohol was'refluxed for thirty minutes and thenconcentrated by boiling to about 25 ml. To the concentrated solutionwasadded ether whereupon a pale yellow solid separated. The mixture wasallowed to cool and the solid collected and dried in vacuo overphosphorus pentoxide at 70C; for 16 hours to yield 9.13 g. of3-chloro-N-(2-diethylaminoethyl)-4- isopropoxymethyl-2,o-dimethylanilinedi-(p-toluenesulfonate), m.p. l23l25C.

EXAMPLE l3 Fermentative enzymatic oxidation of 2-chloro-4-[(2-hydrochloride (33 g.) ,to2-chloro-4-[(2-diethylaminoethyl)methylaminolbenzyl alcoholhydrochloride (7.5 g.) was;

' ene dichloride was taken up with a mixture of 300 ml.

of methanol and 30 ml. of water, the solution filtered and the filtrateextracted with n-hexane. The methanol solution wasconcentrated in vacuoto remove the methanol, the concentrate treated with a small quantity'of benzene, and the benzene removed in vacuo to re-.

move any remaining water. The resulting yellow oil, which included bothdiethylaminoethyl)methylamino]benzaldehyde. was treated with 200 ml. ofmethanol plus sodium borohydride (about 1 g.) 'until a TLC analysisindicated no benzaldehyde product present. The methanol was removed invacuo and the mixture dissolved in 300 ml. of methylene dichloride. Themethylene dichloride solution was washed with three 100 ml. portions ofwater, dried over anhydrous sulfate and concentrated in vacuo to removethe methylene dichloride, thereby yielding about 44 g. ofa yellow oilyproduct. A 5 g. portion of the oily product in methylene dichloridesolution was applied to ten 20 X 40 cm. silica gel plates 1 .mm. inthickness and the plates were developed in ethyl acetate (9):triethylamine (1). The material from the ultraviolet-absorbing bandscontaining the desired benzyl alcohol product (more polar than thestarting toluene derivative) was eluted with about 450 ml. ofchloroform. The chloroform was washed with 200 ml. of water madealkaline with 1 ml. of ION sodium hydroxide solution.- The chloroformsolution was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to yield, as a pale yellow oil, 37 g. of 2-chloro-[(Z-diethylziminoethyl)methylarnino1benzyl alcohol. An additional 5 g.of the above oil was applied to 10 silica gel plates as above and theresulting product was combined with the 3.7 g. of product to yield atotal of 8 g. of 2-chloro-4-[(2-diethylaminoethyl)me thylaminolbenzylalcohol. This product was dissolved in 300 ml. of tetrahydrofuran andthe solution treated dropwise with 9.4 ml. of 6.3N'ethereal hydrogenchloride. The resulting white crystalline precipitate was collected anddried in vacuo at room temperature for using the appropriate4-[amino-(polycarbon-loweralkyl)-amino]-2halotoluene, the corresponding4- [amino-(polycarbon-lower-alkyl)amino]-2-halobenzyl alcohols areobtained, as illustrated, without limiting the foregoing, by thecompounds of Table B.

Table-.13

ca on hal propriate halobenzyl alcohols of Table B also can be preparedby following the procedure described in Example 3A using a correspondingmolar equivalent quantity of the apethyl or other lower-alkyl 4-[amino-(polycarbon-lower-alkyl)-amino]-2-halobenzoate or by following theprocedure described in Examples 5A or 6A using a corresponding molarequivalent quantity of the appropriate4-[amino-(polycarbon-lower-alkyl)- amino]-2'halobenzaldehyde. The4-aminoethylamino- 2-halobcnzyl alcohols of Table B, i.e., CompoundNumbers 1, 2, 4 7-13 and l5-22. alsov can be prepared Tabl g gc r tinued4 c1 ctr (c11 1t(c 1r H CH3 5 01 H CHt'CH )CH N(CH H a 5 01 H :H n(c H HH 7 c1 H. (CH2)2NECH2CH20H H H 8 01 H :11 N(c1{ cH 0H) H H 9 01 H (CHN'H H H 10 01 H (CH2)2NHCH2CH==CH2 H, H

11 01 H (CH N(C H -"n) 1r GH?CH2'OH 12 01 11'. ca CH N H 1; 2 2

"8. 13 01 H CHECHENCSHILO H H 4 b 1 1 01 H (CH NC H H o 15 01 H (cs bucn o H H d. v 16 01 H (CH NC H H a 1 e 17 01 H (cu bm rt H H- 1 I f 18 01H (eu hncu a H H c H 19 01 a (c1r 11 2 5 H H c CH2C(CH3)20H 20 c1 H(CH2)2NC4H8NCH5$ H 'H 21 01 H (CH2)2NH(CH2)6OH H v "-2";im--. 1if???llfllfif ifi zi ff j a) NC H piperidino. b) M 11 pyrrolidinoq c) NC4H8Omorpholinm d) N0 hexamethyleneimimt e) N'3 H 2, S-dimethylpyrrolidinm f)1:0 a 2, 6-dimethylpiperidino.

NC'AH8NCH5 l-methyipiperazino The4-lamino-(polycarbon-lower-alkyl)-amino]-2- following the proceduredescribed in Example 4A by reducing the I corresponding ethyl4-aminoacetylamino 2-halobenzoate, which in turn can be prepared byfollowing the procedure of Example 48 using ethyl2-chloro-4-(chloroacetamido)benzoate and appropriate amine or ammonia(for No. 9).

The 4-lamino-(polycarbon-lower-alkyl)-amino]-2- halobenzyl alcohols andlower-alkyl ethers of our invention' when administered orally tohamsters and Swiss mice infested with Schislosoma mansoni were found toclear completely the animals of the parasitic infection at varying doselevels of compound per kg. of

' fore body weight per day for 5 consecutive days. Some of.

' generally less toxic than the corresponding known toluene derivativeswhen determined by standard procedures in Swiss mice. Illustrative-ofthe schistosomacidal activity of our compounds when determined-asdescribed above are the following data: 2-chloro-4-(2-diethylaminoethylamino)benzyl alchol, oral ED values of 9.0 i 2.4mg./kg./day and l5.0 i 2.8 mg./kg./day in'hamsters and Swiss mice,respectively, compared with respectivevalues of 45 i 16.6 mg;/kg./dayand 13.0 i 2.7 mg./kg./day for the corresponding toluene, derivative,i.e. 2-chloro-4-(2-diethylaminoe thylamino)toluene (HCl salt)2-chloro-4-( 2- diethylaminoethylamino)-3,5-dimethylbenzyl alcoholdi(ptoluenesulfonate), oral ED of 3.7 i 2.0 mg./kg./day in Swiss mice;3-chloro-N-(2- diethylaminoethyl)-4-methoxymethyl-2,6-

dimethylaniline di-(p-toluenesulfonate), oral ED of i 3.4 i 0.5mg./kg./day in Swiss mice; 3-chloro-4-ethoxymethyl-N-(Z-diethylaminoethyl)- 2,6-

We claim: I g l. A compound of the formula: CH OH hal where hal is halo;R and R are each hydrogen or lower-alkyl; NB is N(R)Y-NR,R R is hydrogenor lower-alkyl; Y is C(=O)CH Ryand R are each hydrogen, lower-alkyl,lower-alkenyl having from three to six carbon atoms orlower-hydroxyalkyl having from two to six carbon atoms and having itsconnecting linkage and the hyroxyl group on different carbon atoms, or Rand R taken with N comprehend saturated N- dimethylanilinedi-(p-toluenesulfonate), oral ED of about 12.5 mg./kg./day in hamsters.Illustrative of the toxicity of our compounds are the following acuteintravenous LD values in Swiss mice, LD meaning the dose lethal to 50percent of the mice (10 mice tested each of three dose levels):2-chloro-4-(2 -die thylaminoethylamino)benzyl alcohol, LD of 51 i2-mg./kg., compared with 33 i 2.2 mg./kg. for the corresponding2-chloro-4-(Z-diethylaminoethylamino)toluene.

The subject matter disclosed-and-claimed in the instant application wasneither disclosed nor claimed in said application Ser. No. 444,848, nowUS. Pat. No. 5

heteromonocyclic radicals having from 5 to 6 ring atoms and selectedfrompiperidino', pyrrolidino, morpholino, piperazino, hexamethyleneiminoor such radicals having attached to available ring-atoms from one tothree lower-alkyl groups; lower-alkyl in each instance having from oneto six carbon atoms and beingprimary or secondary.

2. A compound of the formula mi-c-ca NR n 2. o v

where hal is halo, R and R are each hydrogen or lower-alkyl and R and Rare each lower-alkyl, Iower-alkyl in each instance having from one tosix carbon atoms and being primary or secondary.

' 3. A compound according to claim 2-where R and R are each lower-alkyland hal is chloro. 4. 2-Chloro-4-(diethylaminoacetylamino )-3 ,5

dimethylbenzyl alcohol according to claim 3.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION IPATENT N0. 3,355,291

DATED December 17, 1974 |N\/ ENTOR(S) I Sydney Archer and David Rosi Itis Certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, line 4, omit"COMPOSITIONS AND THEIR PREPARATION" Column 1,line 30, "amino[" should read -amino] Column 3, line 17, "of" shouldread or Signed and Sealed this A Second Day Of November 1976 [SEAL]Arrest:

. 1 RUTH C. MASON C. MARSHALL DANN Arresting Office CommissionernfParenrs and Trademarks

1. A COMPOUND OF THE FORMULA:
 2. A compound of the formula
 3. A compoundaccording to claim 2 where R3 and R5 are each lower-alkyl and hal ischloro.
 4. 2-Chloro-4-(diethylaminoacetylamino)-3,5-dimethylbenzylalcohol according to claim 3.